RU2105003C1 - Oxazolidinone derivative or its pharmaceutically acceptable salt, method of treatment of bacterial infections in warm-blooded animals - Google Patents

Abstract

FIELD: chemistry of heterocyclic compounds. SUBSTANCE: product: derivative of oxazolidinone of the formula (I):

or its pharmaceutically acceptable salt where n = 1; A - piperazine ring; Y means -C_1-6-alkyl, -C(O)--C_1-6--alkyl, -C(O)-O--C_1-6--alkyl, benzoyl, 2-benzylhydroxyethoxycarbonyl, 1,4-dioxopentyl, -N-(C_1-4-алкил)₂, piperidyl, morpholinyl, group of the formulas:

; X and Z mean independently C_1-6-alkyl or hydrogen being in any case indicated C_1-6-alkyl can be substituted with one or some substituents taken from F, Cl, Br, CN or OR¹ where R¹ means hydrogen or C_1-4--alkyl; U, V and W mean independently F or hydrogen; R - lower alkyl; q = 0-4. Invention proposes also method of treatment of bacterial infections in warm-blooded animals by administration of compound of the formula (I) at doses 0.1-100 mg/kg body mass/day but preferably at doses 3-50 mg/kg/day. EFFECT: improved method of synthesis. 13 cl, 1 tbl

Description

 The invention relates to an oxazolidinone derivative having a substituted diazine moiety linked to an N-aryl ring. These compounds have antimicrobial activity and are effective against a number of human and animal pathogens, including multiresistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroids and clostridia, and acid-resistant organisms such as Mycobacterium tuberculosis and Mycobacterium avium. These compounds are particularly effective against the latter of these microorganisms, which are known to be responsible for the infection of individuals with AIDS.

 PCT application / US 89/03548 discloses 5'indolinyl-5β-amidomethyloxazolidinones; 3- (substituted on the fused nucleus) phenyl-5β-amidomethyloxazolidinones; and 3- (nitrogen substituted) phenyl-5β-amidomethyloxazolidinones, which can be used as antibacterial agents.

 Various oxazolidinones are also described in other works, including, US patent N 5801600, US patent N 4921869, Gregoty W.A. Et al. J. Med. Chem., 32, 1673-81 (1989); Wang C., et al. Tetrahedron, 45, 1323-26 (1989); and Brittelli et al. J. Med. Chem., 35 (1992).

 Europatent Publication No. 352781 discloses phenyl and pyridyl substituted phenyloxazolidinones.

 European Patent Publication No. 316594 discloses 3-substituted styryloxazolidinones.

 European Patent Publication N312000 discloses phenylmethyl and pyridinylmethyl substituted phenyloxazolidinones.

или к их фармацевтически приемлемым солям,
где Y представляет собой:
a) водород;
b) -C_1-6-алкил или -арил;
c) -OH, -O-C_1-6-алкил, -O-винил, -O-фенил, -O-C(O)-C_1-6-алкил, -O-C(O)-фенил (фенил может быть замещен 1-3 группами, выбранными из F, Cl, -OCH₃, -OH, NH₂ или C_1-4-алкила); или -O-C(O)-O-CH₃;
d) -S-C_1-6-алкил;
e) -SO₂-C_1-6-алкил, -SO₂-N(R³)₂ (где R³ независимо представляет собой водород, C_1-4-алкил, или фенил, который может быть замещен 1-3 группами, выбранными из F, Cl, OCH₃, OH, NH₂, или -C_1-4-алкила);
f) -C(O)-C_1-6-алкил, -C(O)-O-C_1-6-алкил, -C(O)-N(R³)₂, -C(O)-CH(R⁴)N(R³)₂, или -C(O)-CH(R⁴)NH-C(NH)-NH₂ (где R⁴ представляет собой боковую цепь аминокислоты);
g) -N(R³)₂, -N(CH₂)_m (где m = 2-6 и образует циклическую структуру вместе с атомом азота и один или несколько атомов углерода могут быть замещены S, O, или NR³), или

,
(где R⁵ представляет собой OH, OCH₃, CH₂OH, CH₂OCH₃, CO₂CH₃ или CO₂C₂H₅);
h) -C(CH₃)=N-OR;
i)

(где R⁶ является CH₃ или водородом);
j)

(где R⁷ является CH₂ или C(O), а R⁸ является -H или = O);
k)

;
l)

(где p=1 или 2)
m)

;
n)

(где R⁷ представляет собой O, S, S(O), SO₂, CH₂, NH, NCH₃, NC₂H₅, NCHO, NCOCH₃ или NCO₂CH₃);
причем, в каждом случае указанные C_1-6-алкил может быть замещен одним или несколькими заместителями, выбранными из F, Cl, Br, I, OR¹, CO₂R¹, CN, SR¹ или R¹ (где R¹ представляет собой водород или C_1-4-алкил);
X и Z независимо представляют собой C_1-6-алкил, C_3-12-циклоалкил или водород; либо X и Z, взятые вместе образуют мостиковую C_0-3-группу; однако предпочтительно, если X и Z являются водородом;
U, V и W независимо представляют собой C_1-6-алкил, F, Cl, Br, водород или C_1-6-алкил, замещенный одним или несколькими атомами F, Cl, Br или I, а предпочтительно, если U и V являются фтором, а W является водородом;
R представляет собой водород; C_1-12-алкил; C_3-12-циклоалкил; C_1-6-алкокси; C_1-6-алкил, замещенный одним или несколькими заместителями, выбранными из F, Cl, Br, I или OH;
q равно 0-4 включительно.In one of its variants, the present invention relates to a compound of structural Formula I:

or their pharmaceutically acceptable salts,
where Y represents:
a) hydrogen;
b) —C _1-6 alkyl or aryl;
c) -OH, -OC _1-6 -alkyl, -O-vinyl, -O-phenyl, -OC (O) -C _1-6 -alkyl, -OC (O) -phenyl (phenyl may be substituted with 1- 3 groups selected from F, Cl, —OCH ₃ , —OH, NH ₂ or C _1-4 alkyl); or —OC (O) —O — CH ₃ ;
d) -SC _1-6 alkyl;
e) -SO ₂ -C _1-6 -alkyl, -SO ₂ -N (R ³ ) ₂ (where R ^{3 is} independently hydrogen, C _1-4 -alkyl, or phenyl, which may be substituted by 1-3 groups selected from F, Cl, OCH ₃ , OH, NH ₂ , or —C _1-4 alkyl);
f) -C (O) -C _1-6 -alkyl, -C (O) -OC _1-6 -alkyl, -C (O) -N (R ³ ) ₂ , -C (O) -CH (R ⁴ ) N (R ³ ) ₂ , or —C (O) —CH (R ⁴ ) NH — C (NH) —NH ₂ (where R ⁴ is an amino acid side chain);
g) —N (R ³ ) ₂ , —N (CH ₂ ) _m (where m = 2-6 and forms a cyclic structure together with a nitrogen atom and one or more carbon atoms may be substituted by S, O, or NR ³ ), or

,
(where R ⁵ represents OH, OCH ₃ , CH ₂ OH, CH ₂ OCH ₃ , CO ₂ CH ₃ or CO ₂ C ₂ H ₅ );
h) -C (CH ₃ ) = N-OR;
i)

(where R ⁶ is CH ₃ or hydrogen);
j)

(where R ⁷ is CH ₂ or C (O) and R ⁸ is —H or = O);
k)

;
l)

(where p = 1 or 2)
m)

;
n)

(where R ⁷ represents O, S, S (O), SO ₂ , CH ₂ , NH, NCH ₃ , NC ₂ H ₅ , NCHO, NCOCH ₃ or NCO ₂ CH ₃ );
moreover, in each case, said C _1-6 alkyl may be substituted with one or more substituents selected from F, Cl, Br, I, OR ¹ , CO ₂ R ¹ , CN, SR ¹ or R ¹ (where R ¹ represents hydrogen or C _1-4 alkyl);
X and Z are independently C _1-6 alkyl, C _3-12 cycloalkyl or hydrogen; either X and Z taken together form a bridging C _0-3 group; however, it is preferred that X and Z are hydrogen;
U, V and W independently represent C _1-6 alkyl, F, Cl, Br, hydrogen or C _1-6 alkyl substituted with one or more F, Cl, Br or I atoms, and preferably, if U and V are fluorine, and W is hydrogen;
R represents hydrogen; C _1-12 alkyl; C _3-12 cycloalkyl; C _1-6 alkoxy; C _1-6 alkyl substituted with one or more substituents selected from F, Cl, Br, I or OH;
q is 0-4 inclusive.

In formula I, it is preferred that U and V are fluorine and W is hydrogen; either U is fluorine, and V and W are hydrogen. Y is preferably selected from the group consisting of: H, methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2- hydroxyethoxycarbonyl, 2-benzyloxyethoxycarbonyl, 2-methoxyethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, cyanomethyl, 2-cyanoethyl, carbomethoxymethyl, 2-carbomethoxyethyl, 2-fluoroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, phenyl, methyl and more preferably, if Y is methoxycarbonyl or cyanomethyl. It is also preferred that R is methyl, H, methoxy or CHCl ₂ , and n = 1. In addition, it is preferred that the compounds of formula I are optically pure enantiomers having the S configuration at the C5 oxazolidinone ring.

Preferred compounds of the present invention are the following:
(a) 4- (4- (5 - (((Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester;
(b) 4- (4- (5 - (((Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid ethyl ester;
(c) 4- (4- (5 - (((Acetylamino) methyl) -2-oxo-3-oxazolidinyl) phenyl) -1-piperazinecarboxylic acid methyl ester;
(d) N - ((2-oxo-3- (4- (4- (phenylcarbonyl) -1-piperazinyl) phenyl) -5-oxazolidinyl) methyl) acetamide;
(e) N - ((3- (4- (3-fluoro-4- (4- (2-cyanoethyl) -1-piperazinyl)) - phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide;
(f) N - ((3- (4- (3-fluoro-4- (4- (2-hydroxyethyl) carbonyl-1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide;
(g) N - ((3- (4- (3-fluoro-4 - ((phenylcarbonyl) -1-piperazinyl)) - phenyl) 2-oxo-5-oxazolidinyl) methyl) -acetamide;
(h) 4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolinidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid 2-methoxyethyl ester;
(i) 4- [4- [5 (acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazine acetonitrile;
(j) (+/-) - N - [[3- [4- [4-] 4- (1,4-Disoxopentyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl) -acetamide;
(k) (S) -N - [[3- [3-fluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide;
(l) (S) -N - [[3- [3,5-difluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

More preferred are compounds:
(a) 4- [4- [5- (acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinylcarboxylic acid methyl ester;
(i) 4- [4- [5- (acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazineacetoniril.

 In another embodiment, the present invention relates to a method for treating microbial infections in warm-blooded animals by administering to a warm-blooded animal in need of such treatment an effective amount of a compound of formula I as described above. Preferably, said compound is administered in an amount of from about 0.1 to about 100 mg / kg body weight per day, and more preferably from about 3.0 to about 50 mg / kg body weight per day.

 The invention relates to diazinyl oxazolidinones of structural formula I above. These compounds have antimicrobial activity and are effective against a number of pathogens in humans and animals, including multiresistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroids and clostridia, and acid-resistant organisms such as Micobacterium tuberculosis and Micobacterium avium.

As used herein, the definition of “C _1-6 or C _1-12 alkyl” means methyl, ethyl, propyl, butyl, pentyl, hexyl and the like, as well as from isomeric forms.

"Cycloalkyl" means C _3-12 -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and the like, as well as their isomeric forms.

 “Alkoxy” means groups such as methoxy, ethyloxy, butyloxy, and the like, in which 1-6 carbon atoms are bonded to an oxygen atom, as well as their isomeric forms. In addition, in some cases, groups defined herein as “alkoxycarbonyl” in the nomenclature of chemical compounds are designated alkyl esters (eg, methoxycarbonyl and methyl ester).

“Aryl” means a phenyl, pyridyl or naphthyl moiety optionally substituted with one or more substituents selected from F, Cl, Br, I, OR ¹ , CO ₂ R ¹ , CN, SR ¹ , or R ¹ (where R ¹ is hydrogen or C _1-4 alkyl).

 The term "pharmaceutically acceptable salts" means salts that can be used to administer the compounds of the present invention and which are hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate, and the like. These salts may be present as hydrates.

В случае кольца более крупных размеров это кольцо может иметь внутренний мостик и образовывать бициклическую систему, как, например, показано ниже:

Если размер кольца составляет 6 атомов, то это кольцо может быть необязательно замещенным в положениях X и Z алкильными группами, циклоалкильными группами, фторо-группами или мостиковыми алкильными группами, как, например, показано ниже:

В дополнение к вышеуказанным примерам ниже приводится пример альтернативной бициклической системы:

Кольцо B может быть незамещенным или замещенным одним или несколькими атомами галогена, например фтором, хлором, или бромом. Так, например, группы U, V, и W на кольце B могут в различных моделях замещения независимо представлять собой либо атомы водорода, либо атомы галогена.Ring A may have 6-8 atoms, and larger rings may contain two or three carbon atoms between nitrogen atoms, for example:

In the case of a larger ring, this ring may have an internal bridge and form a bicyclic system, as, for example, shown below:

If the ring size is 6 atoms, then this ring may be optionally substituted at the X and Z positions by alkyl groups, cycloalkyl groups, fluoro groups or bridged alkyl groups, as, for example, shown below:

In addition to the above examples, an example of an alternative bicyclic system is provided below:

Ring B may be unsubstituted or substituted by one or more halogen atoms, for example fluorine, chlorine, or bromine. So, for example, the groups U, V, and W on the ring B can, in various substitution models, independently represent either hydrogen atoms or halogen atoms.

 Group Y at the nitrogen atom of ring A can be introduced by standard methods (described below) using commercially available reagents. Preferably, if Y is selected from the group consisting of H, methyl, ethyl, isopropyl, t-butyl, benzyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-hydroxyethoxycarbonyl, 2 -benzyloxyethoxycarbonyl, 2-methoxyethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, cyanomethyl, 2-cyanoethyl, carbomethoxymethyl, 2-carbomethoxyethyl, 2-fluoroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, methylsulfonyl, or phenylsulfonyl; and more preferably, if Y is methoxycarbonyl or cyanomethyl.

The R substituent is preferably methyl, but it may also be H, methoxy or CHCl ₂ .

 Most preferred compounds can be prepared as optically pure enantiomers having the (S) configuration at the C5 oxazolidine ring.

 Optically pure material can be obtained by one of the methods of asymmetric synthesis or by an alternative method of separation of the racemic mixture by selective crystallization of the salt form of the compound; for example, an optically pure amine can be prepared starting from intermediate amine 12 (as described in Example 1 and shown in Scheme 1) using the corresponding optically active acid, such as dibenzoyl tartrate or 10-camphosulfonic acid, followed by treatment with a base.

 Optically pure material can be obtained in another way (for example, as described in the schemes). By treating the commercially available 3-fluorophenyl isocyanate with the commercially available (R) -glycidyl butyrate under Herweh and Kauffmann conditions (Tetrahedron Letters, 1871, 809), the corresponding optically pure oxazolidinone with the desired (S) configuration at the 5-position of the oxazolidinone ring can be obtained. After removal of the butyrate group by treatment with potassium carbonate in methanol or sodium methoxide in methanol, the corresponding alcohol is obtained, which can then be derivatized by standard methods, for example, by mesylation followed by substitution using sodium azide, resulting in azidomethyloxazolidinone. After azide reduction by hydrogenation followed by acylation of the resulting amine by treatment with acetic anhydride and pyridine, the desired optically active acetylaminomethyloxazolidinone is obtained. As for the indicated acetylaminomethyloxazolidinone, the formation of the piperazine moiety is necessary in this case. The nitration of the fluorooxazolidinone derivative gives predominantly a nitro group in the para position at the nitrogen atom of the oxazolidinone ring and in the ortho position of the ring fluorine atom. As a result of reduction of the nitro group by hydrogenation, the corresponding aniline derivative is obtained and after its treatment with bis (2-chloroethyl) amine hydrochloride in the presence of potassium carbonate in boiling diglyme, the optically active piperazine derivative N- [3- [4- [3-fluoro 4- (1-piperazinyl)] phenyl-2-oxo-5-oxazolidinyl] methyl] -acetamide (22), which can then be used to prepare some compounds, examples of which are disclosed herein.

 These compounds can be used to treat microbial infections in humans and other warm-blooded animals by parenteral and oral administration of these compounds to humans or animals. Of the compounds of formula I, the most active, and therefore the most active and preferred, are 4- [4- [5- (acetylamino) methyl-2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid methyl ester (23 ) and 4- [4- [5- (acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazine acetonitrile. In these compounds of general formula I, ring A is the piperazine moiety.

 The pharmaceutical compositions of the present invention can be prepared by mixing the compounds of Formula I of the present invention with a solid or liquid pharmaceutically acceptable carrier and optionally with pharmaceutically acceptable adjuvants and excipients using commonly used standard techniques. examples of solid compositions are powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier is at least one substance which can also serve as a diluent, flavoring agent, solvent, lubricating agent, suspending agent, binder, disintegrating agent and encapsulating agent. examples of inert solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter and the like. Examples of liquid compositions are solutions, suspensions, and emulsions. These compositions may, for example, be prepared as solutions of the compounds of the present invention in water or in solvent systems such as water-propylene glycol and water-polyethylene glycol, optionally containing commonly used coloring agents, flavoring agents, stabilizing agents and thickening agents.

 The pharmaceutical compositions are preferably prepared using standard techniques in the form of a unit dosage form containing an effective or suitable amount of the active ingredient, i.e., a compound of the present invention of formula I.

 The amount of active ingredient, i.e., the compound of the present invention of formula I, in the pharmaceutical composition or its uniform form can vary over a wide range depending on the particular use of the compound, its effectiveness and the desired concentration. Basically, the amount of active ingredient is from 0.5 to 90% by weight of the composition.

 For therapeutic use in the treatment or control of bacterial infections in warm-blooded animals, the compounds of the present invention or their pharmaceutical compositions can be administered orally and / or parenterally in a dose that ensures the preparation and maintenance of appropriate concentrations (i.e., amounts) or levels of active compound in the blood of a warm-blooded animal being treated that are effective against bacterial infection. Basically, such antibacterial effective doses of the active ingredient are from about 0.1 to about 100, and more preferably from about 3.0 to 50 mg per 1 kg of body weight per day. It should be noted that these doses may vary depending on the needs of the patient, the severity of the bacterial infection and the particular compound used. It should also be noted that in order to more quickly achieve the desired level of active ingredient in the patient’s blood, the initially administered dose may exceed the upper limit of the above range; or this initially administered dose may be less than the optimal value, but the daily dose may gradually increase during the course of treatment, depending on the specific situation. If required, the daily dose can be divided into several doses, for example, for administration 2-4 times a day.

 The compounds of the present invention of formula I can be administered parenterally, i.e., by injection, for example, by intravenous injection, or by any other method of parenteral administration. Pharmaceutical compositions for parenteral administration contain a generally pharmaceutically acceptable amount of a compound of formula I in the form of a soluble salt (acid addition salt or basic salt) dissolved in a pharmaceutically acceptable liquid carrier, such as, for example, water for injection, and a buffer for preparing a suitably buffered isotonic a solution having, for example, a pH of about 3.5-6. Suitable buffering agents are, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) - lysine and L (+) - arginine and some other known buffering agents. Typically, the compounds of formula I are dissolved in an appropriate carrier in an amount sufficient to provide a pharmaceutically acceptable concentration for injection in the range of from about 1 mg / ml to about 400 mg / ml of solution. The resulting liquid pharmaceutical composition is administered in such an amount as to result in the desired antibacterial effective dose. The compounds of the present invention of formula I are administered predominantly orally in the form of a solid or liquid dosage form.

The antimicrobial activity of the compounds of the present invention was tested in vivo using a mouse model. A group of female mice (six mice of 18-20 g each) was injected intraperitoneally with bacteria, which were thawed before use in an extract of the brain heart containing 4% brewer's yeast (Staphylococcus aureus) or in the extract of the brain heart (streptococcus) . After 1 h and 5 h after the injection of bacteria (i.e., after infection), antibiotic treatment was carried out in six different doses either by oral intubation or by subcutaneous administration. The number of surviving animals was recorded daily for six days. Then, based on the relative number of dead animals and using probit analysis, the ED ₅₀ value was calculated. Well-known antimicrobial agents were used as a control and for comparison with the compounds of the present invention. The results are presented in the table.

In the table, each of the examples relates to the following compounds:
Example 1. 9- (4- (5- (Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester (23);
Example 3. 4- (4- (5-Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -1-piperazinecarboxylic acid methyl ester;
Example 5. N - ((3- (4- (3-fluoro-4- (4- (2-cyanoethyl) -1-piperazinyl)) phenyl-2-oxo-5-oxazolidinyl) methyl) -acetamide;
Example 6. 4- (4- (5 ((Acetylamino) methyl-2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid 2-hydroxyethyl ester;
Example 7. N - ((3- (4- (3-fluoro-4 - ((phenylcarbonyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide;
Example 10. (+/-) - N - [[3- [4- [4- (1,4-dioxopentyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl) - acetamide;
Example 36. (S) -N - [[3- [3-fluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide;
Example 37. (S) -N - [[3- [3,5-difluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

 General method for the synthesis of 4- (4- (5 - (((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester, methyl ester (23) and ethyl ester 4 - (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid (24) is described in examples 1 and 2, as well as in structural schemes 1 and 2 (For simplicity, the compounds used in these schemes have numerical designations corresponding to specific chemical names). In accordance with these schemes, commercially available difluoronitrobenzene (2) is treated with excess piperazine to give a substitution product 3. After the protection reaction to form the tert-butoxycarbonyl (BOC) derivative 4, a nitro group reduction reaction is carried out using a reagent system containing an ammonium format and Pd / C, whereby an aniline derivative 5 is obtained. After the protection reaction of the obtained compound 5, benzyloxycarbonyl (CBZ) derivative 6 is obtained, which is then subjected to t allylation with the formation of compound 7. As a result of the osmilation of compound 7 according to the method of Kelly and Van Rheenen (Tetrahedron Letters, 1973 (1976), diol 8 is obtained, which, after treatment with potassium carbonate in boiling acetonitrile, is cyclized to form oxazolidinone 9. After mesylation of oxazolidinone 9 in classical the conditions receive mesylate 10, which is then subjected to a mild substitution reaction using sodium azide, resulting in azide 11. This azide 11 is subjected to a reduction reaction by hydrogenation in the presence of Pd / C and get min 12, which is then acylated in situ using acetic anhydride and pyridine to give the BOC-protected oxazolidinone intermediate, namely the 4- (4- (5 - ((acetylamino) methyl) 1,1-dimethylethyl ester -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid.

After the deprotection reaction using trifluoroacetic acid, the key intermediate N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide ( 22), which is then used to obtain analogues. After treating compound 22 with either methyl chloroformate or ethyl chloroformate, preferably under Schotten-Baumann conditions (NaHCO ₃ / acetone-water), 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3- methyl ester oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid 23 and 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid ethyl ester (24) respectively.

 Although the method described above, which is described in Example 1, can be used to obtain all the target compounds, there is another method (albeit less effective), which consists in obtaining intermediates for the preparation of target compounds such as N - ((2 -oxo-3- (4- (4 - ((phenylcarbonyl) -1-piperazinyl) phenyl) -5-oxazolidinyl) methyl) acetamide (20) and methyl ester 4- (4- (5 ((acetylamino) methyl- 2-oxo-3-oxazolidinyl) phenyl) -1-piperazinecarboxylic acid (19), for example, diol 13, obtained from piperazine and p-fluoronitro benzene is treated in the same manner as described for the preparation of diol 8 (see Scheme 1) with one equivalent of mesyl chloride or tosyl chloride, whereby a mono-derivatized compound 14 is obtained together with the same starting material and bis-derivatized material. 14b and treatment of any of these materials with sodium azide, azido alcohol 15 is obtained. After processing this azido alcohol 15 with a base (for cyclization), oxazolidinone 16 is obtained, which it can then be converted to the acetamide derivative 17 in accordance with the reduction-acylation procedure (carried out in one tank) described in Example 1. As shown in the diagram, after solvolytic deprotection of compound 17, N - ((2-oxo-3- (4- (1-piperazinyl) phenyl) -5-oxazolidinyl) methyl) acetamide (18), which is then acylated to obtain two non-fluorinated analogs, namely 4- (4- (5- (methyl (acetylamino) methyl) -2-oxo-4-oxazolidinyl) phenyl-1-piperazinecarboxylic acid (19) and N - ((2-oxo-3- (4- (phenylcarbo nyl) -1-piperazinyl) phenyl) -5-oxazolidinyl) methyl) -acetamide (20).

 Preparation of 4- (4- (5 - (((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester analogues (23) and 4- (4- ethyl ester (5 - ((Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluoro-phenyl) -1-piperazinecarboxylic acid (24) can be easily carried out by simply replacing piperazine with other cyclic amines, and compound 2 with other nitrobenzene derivatives; or by treating N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide (22) (or their analogues) with other acylating or alkylating agents.

 Example 1. 4- (4- (5- (Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester (23).

(a) Preparation of 1- (2-fluoro-4-nitrophenyl) piperazine (3):
A solution of 12.0 g (75.42 mmol) of 3,4-difluoronitrobenzene (2) in 150 ml of acetonitrile was treated with 16.24 g (188.6 mmol) of piperazine and then heated under reflux for 3 hours. The resulting solution was cooled to room temperature and concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ethyl acetate (3x250 ml). After that, the combined organic layers were extracted with water (200 ml) and saturated sodium chloride solution (200 ml), and then dried over sodium sulfate. The resulting solution was concentrated in vacuo, resulting in an orange oily substance, which was chromatographed on 450 g of silica gel (230-400 mesh), eluting first with dichloromethane until the least polar fractions were eluted. Then, elution was continued with 2% (v / v) methanol / chloroform and 10% (v / v) methanol / chloroform. As a result of these stages, 13.83 g (81%) of the desired piperazine derivative (3) were obtained, mp. 68.5-71 ^o C.

(b) Preparation of 1- (tert-butoxycarbonyl) -4- (2-fluoro-4-nitrophenyl) piperazine (4):
A solution of 12.0 g (53.29 mmol) of the nitro derivative (3) in 110 ml of tetrahydrofuran was dropwise treated with a solution of 14.53 g (66.61 mmol) of di-tert-butyl dicarbonate in 110 ml of tetrahydrofuran. After addition, the solution was stirred at room temperature for 24 hours. After that, the solution was concentrated in vacuo, and the residue was chromatographed over 450 g of silica gel (230-400 mesh), eluting with 20% (v / v) ethyl acetate in hexane, 30 % (v / v) ethyl acetate in hexane and then 50% (v / v) ethyl acetate in hexane. As a result, 16.6 g (96%) of the BOC derivative (4) were obtained as a yellow solid, mp. 151-153.5 ^o C.

(c) Preparation of 1- (tert-butoxycarbonyl) -4- (2-fluoro-4-aminophenyl) piperazine (5):
A solution of 1.73 g (5.32 mmol) of nitro compound (4) in 30 ml of methanol and 20 ml of tetrahydrofuran and 10 ml of acetate was treated with 1.68 g (26.59 mmol) of ammonium format and 200 mg of 10% palladium carbon. Immediately after treatment, gas evolution was observed, which stopped after about 30 minutes. After this, the mixture was stirred overnight, and then filtered through celite, and the precipitate formed on the filter was washed with methanol. The filtrate was concentrated in vacuo, dissolved in 50 ml of ethyl acetate and extracted with water (2x30 ml) and saturated sodium chloride solution (30 ml). After drying with sodium sulfate and concentration in vacuo, 1.6 g (approx. 100%) of amine (5) were obtained as a brown solid, which was purified for use in the next step.

(d) Preparation of 1- (tert-butoxycarbonyl) -4- (2-fluoro-4-benzyloxycarbonylamino) piperazine (6):
A solution of 1.57 g (5.32 mmol) of amine 5 and 806 mg (0.84 ml, 6.65 mmol) of dimethylaniline in 25 ml of tetrahydrofuran at -20 ^° C was treated dropwise with benzyl chloroformate (1.0 g, 0.84 ml, 5.85 mmol). After that, the solution was stirred at -20 ^° C for 30 minutes, and then warmed to room temperature. The resulting mixture was diluted with 125 ml of ethyl acetate and extracted with water (2x50 ml) and saturated sodium chloride solution (50 ml). After drying with sodium sulfate and concentration in vacuo, an inhomogeneous material was formed. This material was adsorbed on a silica gel layer and chromatographed on 115 g of silica gel (230-400 mesh), eluting with 18% (v / v) ethyl acetate in hexane, then 25% (v / v) ethyl acetate in hexane and finally 30% (v / v) ethyl acetate in hexane. The result was 1.15 g (50%) of the CBZ derivative (6) as a white solid, mp. 150-153 ^o C.

(e) Preparation of 1- (tert-butoxycarbonyl) -4- (2-fluoro-4-benzyloxycarbonylallylamino) piperazine (7):
A solution of 1.15 g (2.68 mmol) of CBZ-derivative 6 in 10.2 ml of dimethylformamide was treated in portions with 77 mg (129 mg of a 60% solution in oil, 3.21 mmol) of sodium hydride, and then stirred at room temperature within 20 minutes After that, the solution was treated with 356 mg (0.26 ml, 2.95 mmol) of allyl bromide, and then stirred at room temperature for 18 hours. The resulting solution was carefully treated with 75 ml of water and extracted with diethyl ether (3 × 100 ml). The combined organic layers were extracted with saturated sodium chloride solution (100 ml) and dried over sodium sulfate. After concentration in vacuo, an inhomogeneous material was obtained, which was dissolved in dichloromethane and dried with sodium sulfate. The residue was concentrated in vacuo to give an amber-colored oily substance, which was chromatographed over 60 g of silica gel (230-400 mesh), eluting with 25% (v / v) ethyl acetate in hexane. The result was 1.12 g (90%) of the allyl derivative (7) in the form of an oily substance.

(f) Preparation of 1- (tert-butoxycarbonyl) -4- [2-fluoro-4-benzyloxycarbonyl (2,3-dihydroxyprop-1-yl) aminophenyl] piperazine (8):
A solution of 2.18 g (4.64 mmol) of allyl compound 7 and 3.26 g (27.86 mmol) of N-methylmorpholine N-oxide in 21 ml of acetone and 6.4 ml of water was treated with 5 ml of 2.5% (by weight) solution of osmium tetroxide in tert-butyl alcohol. The resulting solution was stirred at room temperature for 24 hours. After that, the solution was cooled to 0 ^° C and 25 ml of a saturated NaHSO ₃ solution was added, then it was stirred at 0 ^° C for 15 minutes and heated to room temperature for 2 hours. the mixture was diluted with 50 ml of water and 50 ml of a saturated solution of sodium chloride, and then was extracted with ethyl acetate (5x100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a brown oily substance. This material was chromatographed over 150 g of silica gel (230-400 mesh), eluting with 10% (v / v) methanol in chloroform. The result was 2.0 g (86%) of diol (8) in the form of a whitish, hygroscopic rigid foam.

(g) Preparation of 3- [3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl] -5-hydroxymethyl-2-oxazolidinone (9):
A solution of 2.0 g (4.01 mmol) of diol 8 in 20 ml of acetonitrile was treated with potassium carbonate (1.1 g, 8.02 mmol) and then heated under reflux for 3 hours. After that, the solution was cooled and concentrated in vacuum. The residue was dissolved in 100 ml of ethyl acetate and the resulting solution was extracted with water (2x50 ml) and then with a saturated solution of sodium chloride (50 ml). After drying with sodium sulfate and concentration in vacuo, an oily substance was formed, which was chromatographed over 80 g of silica gel (230-400 mesh), eluting with 20% (v / v) acetone in dichloromethane. The result was 1.6 g (100%) of oxazolidinone 9 as a white solid, mp. 144-146.5 ^o C.

(h) Preparation of 3- [3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl] -5-methanesulfonyloxymethyl-2-oxazolidinone (10):
To a solution of 375 mg (0.95 mmol) of oxazolidinone 9 and 144 mg (0.20 ml, 1.42 mmol) of triethylamine in 3.8 ml of dichloromethane at 0 ^° C., 130 mg (0.09 ml, 1, 14 mM) methanesulfonyl chloride and then stirred at 0 ^° C. for one hour. The resulting solution was diluted with 30 ml of dichloromethane, and then was extracted with water (2x25 ml) and saturated sodium bicarbonate (25 ml). The resulting residue was dried over sodium sulfate and concentrated in vacuo, to give 440 mg (98%) of mesylate 10 as a white solid, which was pure enough to be able to use this compound in the next step.

(i) Preparation of 3- [3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl] -5-azidomethyl-2-oxazolidinone (11):
A solution of 440 mg (0.93 mmol) of mesylate 10 in 22 ml of acetone was treated with a solution of sodium azide (604 mg, 9.29 mmol) in 6.4 ml of water. The resulting mixture was heated under reflux for 18 hours. Then the mixture was cooled, a solution of 600 mg of sodium azide in 6 ml of water was added, and then it was heated under reflux for another 18 hours. After that, the mixture was cooled again, a solution of 1.2 g of sodium azide was added. in 12 ml of water, and then heated under reflux for 24 hours. After cooling, the mixture was diluted with 60 ml of water and extracted with ethyl acetate (3x75 mm). The combined organic layers were extracted with 100 ml of a saturated solution of sodium chloride, and then dried over sodium sulfate. After concentration in vacuo, 358 mg (92%) of azide 11 was obtained as a white solid (mp 130.5-132.5 ^° C), which was pure enough to be used in the next step.

 (j) Preparation of 3- [3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl] -5-aminomethyl-2-oxazolidinone (12) and 3- [3-fluoro-4-tert-butoxycarbonylpiperazine -1-yl) phenyl] -5-acetylamino-methyl-2-oxazolidinone (21).

 A solution of 1.42 g (3.38 mmol) of azide 11 in 200 ml of ethyl acetate was treated with 400 mg of 10% palladium charcoal and then hydrogenated at atmospheric pressure for 48 hours. The resulting ethyl acetate solution (12) was treated with 1.34 g ( 1.37 ml, 16.9 mmol) of pyridine and 870 mg (0.80 ml, 8.5 mmol) of acetic anhydride, and then stirred at room temperature for 48 hours. After that, the solution was treated with 1.37 ml of pyridine and 0 , 8 ml of acetic anhydride, and then stirred at room temperature for another 48 hours. This solution was filtered through celite, and the precipitate formed on the filter romyvali ethyl acetate. The filtrate was washed with water (4x50 ml), 1.0 M copper sulfate solution (50 ml) and again with water (50 ml). After drying with sodium sulfate and concentration in vacuo, a foamy substance was obtained, which was dissolved in dichloromethane and stirred for an hour with a saturated solution of sodium bicarbonate.

The resulting mixture was extracted with dichloromethane, and the combined organic layers were dried with sodium sulfate and concentrated in vacuo, resulting in an amber-colored oily substance. This material was chromatographed over 74 g of silica gel (230-400 mesh), eluting with 2% (v / v) methanol in dichloromethane and then 5% (v / v) methanol in dichloromethane. The result was 1.19 g (81%) of 3- (3-fluoro-4-tert-butoxycarbonylpiperazin-1-yl) phenyl) -5-acetylaminomethyl-2-oxazolidinone (21) as an off-white rigid foam (mp 162-164 ^° C).

 (k) Preparation of N - ((3- (4- (3-fluoro-4- (1-piperazine)) phenyl) -2-oxo-5-oxazolidinone) methyl) acetamide (22).

A solution of 1.19 g (2.73 mmol) of the BOC-derivative [3- (3-fluoro-4-tert-butoxycarbonylpiperazin-1-yl) phenyl) -5-acetylaminomethyl-2-oxazolidinone (21)] in 40 ml of dichloromethane at 0 ^° C., 15 ml of trifluoroacetic acid were treated. This solution was stirred for 30 minutes at 0 ^° C. and then warmed to room temperature, after which the reaction was completely completed. The resulting solution was concentrated in vacuo, and the residue was diluted with ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, after which it was seen that most of the product remained in the aqueous layer. After that, the aqueous layer was adjusted to pH = 14 by adding a 50% NaOH solution. After extraction with ethyl acetate, drying with sodium sulfate and concentration in vacuo, 179 mg of an amber-colored oily substance was obtained. This material was subjected to circular chromatography on 2 mm plates, eluting with 10% (v / v) methanol in chloroform and then with 15% (v / v) methanol in chloroform. The result was 125 mg (79%) of N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide (22) in as a whitish rigid foam.

 (I) Preparation of 4- (4- (5 - ((Acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester (23).

A solution of 120 mg (0.36 mmol) N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2- oxo-5-oxazolidinyl) methyl) -acetamide and 60 mg ( 0.71 mmol) of solid sodium bicarbonate in 1.5 ml of acetone and 0.7 ml of water at 0 ^° C. were treated with 37 mg (30 μl, 0.39 mmol) of methyl chloroformate. After that, the solution was stirred for 1 h at 0 ^o C, and then diluted with 20 ml of water. The resulting mixture was extracted with ethyl acetate (30 ml), and the organic layer was extracted with water (2x10 ml) and saturated sodium bicarbonate solution (10 ml). The solution was then dried over sodium sulfate and concentrated in vacuo to give 95 mg of a crude product. This crude product was subjected to radial chromatography on 2 mm plates, eluting with 33% (v / v) acetone in dichloromethane and then 50% (v / v) acetone in dichloromethane. As a result, 81 mg (57%) of 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester was obtained as a white solid mp 177-179 ^o C.

 Example 2. Ethyl 4- (4- (5 - (((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid ester (24).

The same procedures were used as described in Example 1 (steps ak). Solution 100 mg (0.30 mmol) N- (33- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide (23) (product from step (k) described above) and 50 mg (0.59 mmol) of solid sodium bicarbonate in 2 ml of acetone and 1 ml of water at 0 ^° C., 35 mg (31 µl, 0.33 mmol) of ethyl chloroformate were treated. The resulting solution was stirred at 0 ^° C. for 2 hours and then warmed to room temperature for 18 hours. This solution was diluted with 30 ml of water and extracted with ethyl acetate (40 ml). The organic layer was washed with 30 ml of water and 30 ml of a saturated solution of sodium bicarbonate. After drying with sodium sulfate and concentration in vacuo, a white solid was obtained. This material was subjected to radial chromatography on 22 mm plates, eluting with 2% (v / v) methanol in chloroform. Thus, 70 mg (58%) of 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid ethyl ester (24) was obtained as white solid, mp 224-226 ^o C.

 Example 3. Methyl ester of 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) phenyl) -1-piperazinecarboxylic acid.

 The target compound was obtained in accordance with the procedure described in example 1, except that instead of the starting material (3,4-difluoronitrobenzene (2)) 4-fluoronitrobenzene was used.

 Example 4. N - ((2-Oxo-3-4- (4-phenylcarbonyl) -1-piperazine) phenyl) -5-oxazolidinone) methyl) acetamide.

 The target compound was obtained in accordance with the procedure described in example 2, except that the starting material (3,4-difluoronitrobenzene (2)) was replaced with 4-fluoronitrobenzene.

 Example 5. N - ((3- (4- (3-fluoro-4- (4- (2-cyanoethyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinone) methyl) -acetamide.

Solution 75 mg (0.22 mmol) N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl-2-oxo-5-oxazolidinyl) methyl) -acetamide (22) (example 1, part k) in 5 ml of methanol, 13 mg (17 μl, 0.25 mmol) of acrylonitrile were treated and then heated under reflux for 3 hours, after which the solution was cooled and concentrated in vacuo. mm plates, eluting with 5% (v / v) methanol in chloroform, 84 mg (97%) of the desired nitrile were obtained, N - ((3- (4- (3-fluoro-4- (4 - (2-cyanoethyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide and in the form of a white solid product, mp 125-130 ^o C.

 Example 6. 2- Hydroxyethyl ester of 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid.

Solution 208 mg (0.25 mmol) N- (93- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide (22) (product Example 1, part k) in 3 ml of acetone and 2 ml of water was treated with sodium bicarbonate (21 mg, 0.25 mmol) and then cooled to 0 ^° C. The resulting mixture was treated with 54 mg of a solution (0.25 mmol) of 2-benzyloxyethyl chloroformate in 2 ml of acetone. After this, the solution was allowed to warm to room temperature for 22 hours, and then 30 ml of ethyl acetate was diluted and extracted with water (3x30 ml) and saturated sodium bicarbonate solution (20 ml). This solution was dried with sodium sulfate and concentrated in vacuo to give a white solid. This material was subjected to radial chromatography on 4 mm plates (eluent: 20% (v / v) acetone in dichloromethane). As a result of these procedures, 113 mg (approx. 100%) of chloroformate, 4- (4- (5 - ((acetylamino) methyl) 2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid 2-hydroxyethyl acid were obtained ester in the form of a white solid, so pl. 121-123 ^o C. A solution of the obtained material in 5 ml of methanol was treated with 35 mg of 10% palladium carbon, and then subjected to hydrogenolysis for 1 h at a pressure of 1 ATM. The resulting mixture was filtered through celite, and the precipitate formed on the filter was washed with methanol. The filtrate was concentrated in vacuo to give a white solid. This material was subjected to radial chromatography on 2 mm plates, eluting with 5% (v / v) methanol in chloroform and then 10% (v / v) methanol in chloroform. The result was 76 mg (82%) of hydroxyethyl chloroformate, 2- hydroxyethyl ester 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid as a white solid product, so pl. 203-206 ^o C.

 Example 7. N - ((3- (4- (3-fluoro-4 - ((phenylcarbonyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) -acetamide.

In accordance with the procedure described in example 1, the target compound was obtained from 100 mg (0.297 mmol) N - ((3- (4- (3-fluoro-4- (1-piperazinyl)) phenyl) -2-oxo-5 -oxazolidinyl) methyl) acetamide (22) (product of Example 1, part k), except that methyl chloroformate (starting material) was replaced with benzoyl chloride. As a result of this procedure, 73 mg (56%) of N - ((3- (4- (3-fluoro-4- (phenylcarbonyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) - acetamide in the form of a fine white powder, mp 184-187 ^o C.

 Example 8. 4- [4 - [(5 - [(Acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid 2-methoxyethyl ester.

A solution of 75 mg (0.22 mmol) of the piperazine derivative 22 in 4 ml of acetone and 2 ml of water was treated with sodium bicarbonate (2 mg, 0.25 mmol), then cooled to 0 ^° C. and a solution of 35 mg (0.25 mmol) was added. ) 2-methoxyethyl chloroformate in 0.5 ml of tetrahydrofuran. The resulting mixture was warmed to room temperature for 22 hours. After that, the mixture was diluted with 30 ml of ethyl acetate, and then was extracted with water (3 × 20 ml) and saturated sodium bicarbonate solution (20 ml). The combined aqueous layers were extracted with ethyl acetate (2 x 20 ml), and the combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white solid. The resulting material was subjected to radial chromatography on 4 mm plates, eluting first with 20% (v / v) acetone in dichloromethane and then with 30% (v / v) acetone in dichloromethane. The result was 92 mg (96%) of the desired compound as a white solid.

 Example 9. 4- [4- [5 (Acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazineacetonitrile.

A solution of 75 mg (0.22 mmol) of the piperazine derivative 22 in 4 ml of acetone and 2 ml of water was treated with 21 mg (0.25 mmol) of sodium bicarbonate and then cooled to 0 ^° C. The resulting mixture was treated with 226 mg (190 µl, 3 , 0 mM) of freshly prepared distilled chloroacetonitrile, after which this mixture was left to warm to room temperature for 60 hours. The resulting solution was diluted with 35 ml of ethyl acetate, and then extracted with water (3 × 20 ml) and saturated sodium bicarbonate solution (20 ml). The combined aqueous layers were extracted with ethyl acetate (3 x 20 ml), and the combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white solid. This material was subjected to circular chromatography on 4 mm plates (eluent: 5% (v / v) methanol in chloroform). As a result of these procedures, 80 mg (96%) of the desired nitrile was obtained as a shiny white solid.

Example 10. (+/-) - N - [[3- [4- [4- (1,4-dioxopentyl) -1-piperazinyl] -2-oxo-5-oxazolidinyl] methyl) acetamide (Y = MeCO ( CH ₂ ) ₂ -CO-, monoF, racemic).

The compound of Example 1 (step k) (0.104 g) was treated with 0.041 g of levulinic acid, 0.083 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 0.005 g of N, N-dimethylaminopyridine in 2 ml of pyridine. The resulting mixture was stirred for 2 days at 20 ^° C. After aqueous extraction using methylene chloride, 0.139 g of residue was obtained. This material was purified by medium pressure liquid chromatography (HPLC) on silica gel (eluent: 5% (v / v) methanol in ethyl acetate), whereby 0.118 g of a white solid was obtained, so pl. 148-150 ^o C.

Example 11. N - [[3- [4- [4- (1,4-dioxopentyl) -1-piperazinyl] -3,5-difluoropentyl] -2-oxo-5-oxazolidinyl] methyl) -acetamide, (S ) - (Y is as defined above; diF, optically active)
In accordance with the General procedure described in example 10, but using the trifluoroacetic salt of piperazine U-99472 (prepared as described below), 0.291 g of salt was obtained. This salt was subjected to medium pressure liquid chromatography, and then subjected to preparative thin layer chromatography (1000 μm, eluent: 20% acetone / methylene chloride (vol./about.), Resulting in 0.103 g of a foamy white solid, so pl. 52-56 ^o C.

Example 12. (+/-) - N - [[3- [4- [4 - [(1-oxo-6-oxa-7-phenyl) heptyl] -1-piperazinyl] -3-fluorophenyl] -2- oxo-5-oxazolidinyl] methyl) acetamide (Y = PhCH ₂ O (CH ₂ ) ₄ CO-).

The general procedure described in Example 10 was used, except that levulinic acid was replaced with 5-benzyloxyvaleric acid (0.074 g), whereby 0.101 g of compound was obtained. This compound was subjected to medium pressure liquid chromatography (eluent: 10% methanol in ethyl acetate) to obtain 0.130 g of the target compound, TLC: R _f = 0.24 (eluent: 10% methanol in ethyl acetate, v / v) .

Example 13. (+/-) - N - [[3- [4- [4- (1-oxo-5-hydroxypentyl) -1-piperazinyl] -3-fluoropentyl] -2-oxo-5-oxazolidinyl] methyl ) - acetamide (Y = HO (CH ₂ ) ₄ CO-).

The compound of example 12 (66 mg) was dissolved in 5 ml of methanol, the reaction vessel was purged and filled with nitrogen (3 times). 0.034 g of palladium black was added to the mixture, and the reaction vessel was purged again and filled with hydrogen from a balloon (3 times). The resulting mixture was stirred in a hydrogen atmosphere for 3 hours, and then filtered through diatomaceous earth, washed with methanol, and the filtrate was evaporated. The resulting residue was triturated with chloroform, and the precipitated white solid precipitate was collected and the target compound was obtained, so pl. 171-172 ^° C. TLC: R _f = 0.07 (10% methanol in ethyl acetate, v / v).

Example 14. N - [[3- [3,5-difluoro-4- [4- [5-R, S-methyl - [(1,3-di-oxa-2-oxo) cyclopentyl]]] -1 -piperazinyl] phenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide, - (5S) (Y = cyclic carbonate: optically active with oxazolidinone, but having a racemate with cyclic carbonate, diF)
BOC-piperazine, diF, optically active compound (0.094 g) was treated with 1.0 ml of trifluoroacetic acid in 1.5 ml of methylene chloride at 0 ^° C. for 50 minutes, and then heated to 20 ^° C. The resulting volatiles were removed in vacuo and received a red oily substance (piperazine trifluoroacetate U-99472). To this material was added 0.036 g of chloroethylmethylene carbonate and 0.069 g of potassium carbonate in acetonitrile, after which the mixture was heated under reflux for 1 day. The mixture was then filtered and evaporated in vacuo to give a yellow oily substance. The resulting residue was purified by silica gel GCSD (eluting with a gradient of 5-10% methanol in methylene chloride, v / v) and then subjected to preparative TLC (eluent: 7% methanol in methylene chloride), whereby 0.022 g of white was obtained solid, mp 106-111 ^o C.

Example 15. N - [[3- [3,5-difluoro-4- [4- (1-oxo-2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, (S) - (Y = MeOCH ₂ CO optically active, diF).

To a solution of piperazine trifluoroacetate salt (0.192 g) in 3 ml of methylene chloride and 1.0 ml of triethylamine in a nitrogen atmosphere and at 0 ^° C., 0.071 g of methoxyacetyl chloride was added. The resulting mixture was stirred at 0 ^° C. and then subjected to aqueous extraction using methylene chloride. The organic layer was dried with magnesium sulfate and concentrated to a volume of 5-10 ml, then cooled, and the resulting solid residue was collected and recrystallized from ethyl acetate. The result was 44 mg of a white solid product, mp. 239-241 ^o C.

Example 16. (+/-) - N - [[3- [4- [4- (N-carbobenzyloxy) -2-amino-1-oxoethyl) -1-piperazinyl]] -3-fluorophenyl] -2 -oxo-5-oxazolidinyl] methyl] acetamide (Y = Ph CH ₂ O ₂ CNHCH ₂ CO racemic, monoF).

To the compound of Example 1 k (0.115 g), 0.085 g of N-carbobenzyloxyglycine in 4 ml of tetrahydrofuran and 2 ml of water was added, and then the pH was adjusted to 4 by adding 3 N. hydrochloric acid and 0.203 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. After this, the mixture was stirred at 20 ^° C for one hour, another 0.101 g of N-carbobenzyloxyglycine and 0.225 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide were added, and pJ was adjusted to 3-4 and 5 by adding 2n sodium hydroxide . The resulting mixture was stirred overnight. Thereafter, the mixture was subjected to aqueous extraction using ethyl acetate, the organic layers were concentrated, and the residue was purified by concentration from methylene chloride and methanol. As a result of trituration with methanol, 0.042 mg of a white solid was obtained, mp. 189-191 ^o C.

 Example 17. (S) -N - [[3- [4- [4- (cyanomethyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide (U-97665).

 In the subsequent steps, the preparation of a mono-F-substituted product of the present invention is disclosed.

(a) 1,1-Dimethylethyl ester of (S) -4- [4- [5- (hydroxymethyl) -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid (2):
in a solution of 7.5 g (17.5 mmol) of CBZ-derivative 1 in 240 ml of tetrahydrofuran at -78 ^° C, 12.0 ml (1.6 M, 19.25 mmol) of n- were added dropwise over about 3 minutes butyl lithium in hexane. Then this solution was stirred at -78 ^° C for 30 minutes; thereafter, 2.78 g (2.73 ml, 19.25 mmol) of pure R - (-) - glycidyl butyrate (dropwise) was added over about 5 minutes, and the solution was warmed to 0 ^° C. Then, the solution was warmed to room temperature for 18 hours. The resulting mixture was diluted with dichloromethane and extracted with water, and then with a saturated aqueous solution of sodium chloride. The organic layer was dried with sodium sulfate and concentrated to give a gummy residue. This residue was recrystallized from hot ethyl acetate with the addition of a certain amount of hexane, whereby 6.4 g (93%) of the desired product was obtained, mp. 130.5-133 ^o C.

(b) (S) -4- [4- [5- (methanesulfonyloxymethyl) -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (3):
a solution of 2.88 g (7.28 mmol) of alcohol (2) in 32 ml of dichloromethane at 0 ^° C was treated with 1.29 g (1.77 ml, 12.7 mmol) of triethylamine, and then 1.04 g (0 70 ml, 9.10 mmol) methanesulfonyl chloride. The resulting solution was stirred for 15 minutes at 0 ^° C., after which it was diluted with dichloromethane and extracted with water. This solution was dried over sodium sulfate and concentrated in vacuo to give 3.4 g (98%) of mesylate 3 as a light pink solid (high resolution mass spectroscopy: calculated for C ₂₀ H ₂₈ FN ₃ O ₇ S: 4731632, found : 4731631) clean enough for use in the subsequent step.

(c) 1,1-Dimethylethyl ester of (S) -4- [4- [5- (azidomethyl) -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid (4):
a solution of 16.8 g (35.5 mmol) of mesylate 3 in 400 ml of dimethylformamide was treated with 11.5 g (177.5 mmol) of sodium azide and then heated for 16 hours at 60 ^° C. The resulting solution was diluted with ethyl acetate and extracted with water . The organic layer was dried with sodium sulfate and concentrated in vacuo, whereby 14.9 g (100%) of azide 4 was obtained as a pale yellow solid (mp 101-104 ^° C), pure enough for use in the next step .

(d) (S) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid 1,1-dimethylethyl ester (5) :
a solution of 14.92 g (35.5 mmol) of azide 4 in 200 ml of ethyl acetate was treated with 2 g of 10% palladium on carbon and then hydrogenated for 24 hours under a pressure of 1 atm. The reaction flask was purged with nitrogen, and then 14.0 g (14.4 ml, 177.5 mmol) of pyridine and 9.1 g (8.4 ml, 88.8 mmol) of acetic anhydride were added. The resulting mixture was stirred at room temperature for 72 hours, after which it was filtered through celite. The filtrate was extracted with water, 1 N. a solution of copper sulfate, dried, concentrated in vacuo and received a brownish solid. This material was purified by silica gel chromatography; received 12.7 g (82%) of product 5 in the form of a powdered white solid, so pl. 153-158 ^o C.

(e) (S) -N - [[3- [4- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide:
35 ml of trifluoroacetic acid at 0 ^° C. were treated with 5.0 g (11.46 mmol) of the BOC derivative, and then warmed to room temperature for one hour. The resulting solution was concentrated in vacuo and a residue was obtained, which was dissolved in water and stirred with 125 ml of AGI-18 ion-exchange resin (OH ^- form) for 2.5 hours. Then, the resin was removed by filtration, washed with water, and the combined filtrates were dried by freezing. , resulting in a gain of 2.7 g (69%) of the desired compound in the form of white solid flakes, so pl. 73-76 ^o C.

(f) (S) -N - [[3- [4- [4- (cyanomethyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide:
a solution of 2.42 g (7.2 mmol) of the described compound of step (e) in 242 ml of acetone and 74 ml of water was cooled to 0 ^° C and treated with 1.20 g (14.4 mmol) of sodium bicarbonate, after which 26 2 g (22.0 ml, 0.35 M) of chloroacetonitride. The resulting solution was warmed to room temperature for 36 hours. The mixture was diluted with ethyl acetate and extracted with water and then with a saturated solution of sodium chloride. After drying with sodium sulfate and concentration in vacuo, a whitish solid was obtained, which was purified by silica gel chromatography (eluent: methanol / chloroform solvent system). The result was 2.2 g (82%) of the target compound in the form of a white solid flocculent substance, so pl. 166-167 ^o C.

 Example 18. (S) -N - [[3- [4- [4- (cyanomethyl) -1-piperazinyl] -3,5-difluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

In accordance with the procedure described in example 17 (except that the monofluoro derivative of example 17 (e) was replaced with the difluoropiperazine derivative ((S) -N - [[3- [3,5-difluoro-4- (1- piperazinyl) phenyl] -2-oxo-5,5-oxazolidinyl] methyl] -acetamide)), the target compound was obtained in the form of a white powder with mp 150-154 ^o C.

 Example 19. (+) - N - [[3- [4- [4- (2-cyanoethyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

A solution of 75 mg (0.22 mmol) of the racemic mixture of Example 17 (step e) in 5 ml of methanol was treated with 13 mg (17 μl, 0.25 mmol) of acrylonitrile, and then heated under reflux for 3 hours. The solution was concentrated in vacuo. . The resulting residue was subjected to circular chromatography (eluent: 5% (v / v) methanol in chloroform). The result was 84 mg (97%) of the target compound as a white solid, mp 125-130 ^o C.

 Example 20. (+) - N - [[3- [4- [4- (2-cyano-2-propyl) -1-piperazidinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide .

A solution of 75 mg (0.22 mM) of the racemic mixture of Example 17 (e) in 1 ml of dry acetonitrile was sequentially treated with 5 mg (33 μl, 0.45 mm) of dry acetone and 44 mg (59 μl, 0.45 mm) of trimethylsilyl cyanide. The resulting solution was heated under reflux for 18 hours, and then diluted with ethyl acetate and extracted with water. Drying with sodium sulfate and concentration in vacuo gave a brownish solid. This material was subjected to circular chromatography, eluting with 5% (v / v) methanol in dichloromethane. The result was 36 mg (40%) of the target compound as a white solid, mp 139-143 ^o C.

 Example 21. (S) -N - [[3- [4- [4- (4-cyanotetrahydropyran-4-yl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl acetamide .

A solution of 50 mg (0.15 mmol) of the product of example 17 (e) in 2 ml of dry acetonitrile was treated sequentially with 3 mg (0.02 mmol) of anhydrous zinc chloride, 30 mg (28 μl, 0.30 mmol) of tetrahydropyran-4-one 'a and 29 mg (40 μl, 0.30 mmol) of trimethylsilyl cyanide. The resulting solution was heated under reflux for 30 hours, diluted with ethyl acetate and extracted with water. After drying with sodium sulfate and concentration in vacuo, a pale yellow solid was obtained. This material was subjected to circular chromatography, eluting with methanol / dichloromethane. The result was 24 mg (36%) of the target compound in the form of a white solid, so pl. 134-137 ^o C.

 Example 22. (+) - N - [[3- [3-fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide.

A solution of 0.250 g (0.267 mmol) of the racemic product of Example 17 (e) in 4 ml of THF and 2 ml of water was treated with 11 mg (9 μl, 0.243 mmol) of formic acid and the pH was adjusted to 4.5 by adding 0.1 N. aqueous hydrochloric acid. After this, the mixture was added to 153 mg (0.80 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in 1 ml of water, stirring at room temperature. After that, the mixture was adjusted to pH = 4.5 by adding 2N sodium hydroxide solution and 0.1 N hydrochloric acid solution. After approximately 1 hour stirring, more carbodiimide (100 mg, 0.54 mmol) and formic acid (30 mg, 0.80 mmol) were added, after which the mixture was stirred at room temperature for 16 hours. This mixture was diluted with water and extracted with ethyl acetate. . The organic layer was extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over sodium sulfate and concentrated in vacuo. The resulting white solid was chromatographed on silica gel (eluent: methanol / methylene chloride) to give 0.094 g (97%) of the target compound as a white solid, mp. 190-193.5 ^o C.

 Example 23. Methyl ester of (S) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidine)] 2-fluorophenyl] -1-piperazinecarboxylic acid.

A solution of the product of example 17 (step e) in 22 ml of acetone and 11 ml of water was treated with 150 mg (1.80 mmol) of sodium bicarbonate and cooled to 0 ^° C., then 0.170 g (0.14 ml, 1.80 mmol) was added. methyl chloroformate. After 2 hours, the mixture was diluted with ethyl acetate and extracted with water and a saturated solution of sodium chloride. After drying with sodium sulfate and concentration in vacuo, a white solid was obtained, which was purified by silica gel chromatography (eluent: acetone and methylene chloride system). The result was 0.494 g (77%) of the target compound as a white solid, mp 179.5-182 ^o C.

 Example 24. Methyl ester of (S) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidine)] 2,6-difluorophenyl] -1-piperazinecarboxylic acid.

In accordance with the procedure described in example 23, except that the product of example 17 (e) was replaced with difluoropiperazine, the desired compound was obtained in the form of a white powder, mp 175-178 ^o C.

 Example 25. (+) - N - [[3- [4- [3-fluoro-4 - [(phenylcarbonyl) -1-piperazinyl]] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

In accordance with the procedure described in example 23 (using the racemic mixture of example 17 (e), except that methyl chloroformate was replaced with benzoyl chloride, the title compound was obtained in the form of a white powder, mp 184-187 ^° C.

 Example 26. 2-Methoxyethyl ester (+) - 4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidine)] 2-fluorophenyl] -1-piperazinecarboxylic acid.

A solution of 75 mg (0.22 mmol) of the monofluoropiperazine derivative of Example 25 in 4 ml of acetone and 2 ml of water was treated with 21 mg (0.25 mmol) of sodium bicarbonate and then cooled to 0 ^° C. The resulting solution was treated with 35 mg (0.25 mM) solution of 2-methoxyethyl chloroformate in 0.5 ml of tetrahydrofuran. After this, the solution was warmed to room temperature for 22 hours. This solution was diluted with ethyl acetate and extracted with water, saturated sodium bicarbonate solution, and then saturated sodium chloride solution. The organic layer was dried with sodium sulfate and concentrated in vacuo to give a white solid residue. This residue was subjected to circular chromatography, eluting with 30% (v / v) acetone / dichloromethane). The result was 92 mg (96%) of the target compound as a white solid, mp 166-167 ^o C.

 Example 27. 2-Methoxyethyl ester of (S) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidine)] -2,6-difluorophenyl] -1-piperazinecarboxylic acid.

In accordance with the procedure described in example 26, except that the product of example 17 (e) was replaced with difluoropiperazine 7, the desired compound was obtained as a white solid, mp 154.5-156 ^o C.

 Example 28. 2- (Phenylmethoxy) ethyl ester of (±) -4- [4-5 - [(acetylamino) methyl] -2-oxo-3-oxazolinyl-2-fluorophenyl] -1-piperazinecarboxylic acid.

A solution of 208 mg (0.25 mmol) of the product of example 25 in 3 ml of acetone and 2 ml of water was treated with sodium bicarbonate (21 mg, 0.25 mmol) and then cooled to 0 ^° C. After that, the mixture was again treated with 54 mg (0 , 25 mmol) of a solution of 2- (phenylmethoxy) ethyl chloroformate in 2 ml of acetone. This solution was allowed to warm to room temperature for 22 hours, after which it was diluted with ethyl acetate and extracted with water and saturated sodium bicarbonate solution. Drying with sodium sulfate and concentration in vacuo gave a white solid, which was subjected to circular chromatography (eluent: 20% (v / v) acetone in dichloromethane). Thus, 113 mg (100%) of the target compound were obtained in the form of a white solid with a melting point of 121-123 ^o C.

 Example 29. 2- (Phenylmethoxy) ethyl ester of (S) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolinyl-2,6-difluorophenyl] -1-piperazinecarboxylic acid.

In accordance with the procedure described in example 28, except that the compound of example 17 (e) was replaced with difluoropiperazine 7, the target compound was obtained as a white solid, mp 108-110 ^o C.

 Example 30. 2-Hydroxyethyl ester of (±) -4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolinyl-2,6-difluorophenyl] -1-piperazinecarboxylic acid.

A solution of 113 mg of the compound of Example 28 in 5 ml of methanol was treated with 35 mg of 10% palladium carbon, and then hydrogenated at atmospheric pressure for one hour. The resulting mixture was filtered through celite, and the filter cake was washed with methanol. The filtrate was concentrated in vacuo to give a white solid. This material was purified by circular chromatography, eluting with a solvent system of methanol and chloroform. The result was 76 mg (82%) of the target compound as a white solid, mp 203-206 ^o C.

 Example 31. [S- (R)] -N - [[3- [3,5-difluoro-4- [4 - [(tetrahydro-2-furanyl) carbonyl] -1-piperazinyl] phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide.

A solution of 100 mg (0.28 mmol) of the ((S) -N - [[3- [3,5-difluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-5-oxazolidinyl] methyl difluoropiperazine derivative ] -acetamide) and 144 mg (1.25 mM) of (R) -2-tetrahydrofuran acid in 4 ml of tetrahydrofuran and 2 ml of water were adjusted to pH = 4.5 by adding 2 N NaOH solution. This solution was treated with a solution of 324 mg (1.69 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in 2 ml of water. Then this solution was maintained at pH = 4.6 by adding 2 N. NaOH solution, stirring at room temperature for 1.5 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a brownish solid, which was subjected to circular chromatography (eluent: methanol / dichloromethane solvent system). The result was 106 mg (83%) of the desired amide as a white solid, mp. 198-200 ^o C.

 Example 32. (S) -N - [[3- [3,5-difluoro-4- [4- [2- (1-piperidinyl) ethyl] -1-piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide.

 In the subsequent steps, the preparation of the difluoro intermediate compounds of the present invention is disclosed.

 (a) 2,6-Difluoro-4-nitrobenzene (trifluoromethane) sulfonate.

2,6-Difluoro-4-nitrophenol (31.55 g, 180.19 mmol) was combined with methylene chloride (300 ml) and pyridine (29.15 ml, 360.38 mmol). The resulting suspension was cooled to 0 ^° C in an ice bath and treated dropwise with trifluoroacetic acid anhydride (31.8 ml, 189.2 mmol) for 45 minutes. The reaction mixture was allowed to stir at 0 ^° C. for 2 hours and then stored overnight in a refrigerator at 5 ^° C. The completion of the reaction was monitored by TLC (15% EtOAc / Hexane, Shortwave UV). After this, the reaction mixture was concentrated under reduced pressure, and then treated with water (50 ml) and ethyl acetate (50 ml). This mixture was transferred to a separatory funnel with 100 ml of ethyl acetate and washed with 1N. hydrochloric acid solution until the washings became acidic (2x100 ml). The aqueous phases were back extracted with ethyl acetate (2 x 100 ml). The combined ethyl acetate extracts were again combined and washed with 1N hydrochloric acid solution (400 ml), after which it was washed once with brine (400 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 54.092 g of a red-golden oily substance. Although this substance was pure, as evidenced by NMR analysis, it was combined with crude products from other reactions and chromatographed on a silica gel column (550 g) packed with 5% ethyl acetate. After elution with 2 L of 5% ethyl acetate and 2 L of 10% ethyl acetate, the desired compound was obtained (95% complete yield) as a pale yellow oily substance, VRMS (M ⁺ ) for C ₇ H ₂ F ₅ NO ₅ S: calculated: 3069574; Found: 3069590.

 (b) 1- (tert-Butoxycarbonyl) -4- (2,6-difluoro-4-nitrophenyl) piperazine.

A solution of 2,6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate (55 g, 179 mmol) in dry DMF (275 ml) was treated with 1- (tert-butoxycarbonyl) piperazine (45.71 g, 250 mmol). The resulting clear yellow solution turned orange after addition of N, N-diisopropylethylamine (47 ml, 269 mmol). The reaction mixture was refluxed for 15 hours under nitrogen. The completion of the reaction was monitored by TLC (30% EtOAc / hexane, shortwave UV). The reaction mixture was concentrated to dryness and combined with the crude product from another reaction for purification. This crude material was dissolved in hot methylene chloride (420 ml; some solids not related to this product did not dissolve), and then chromatographed on 3 separate columns (2 columns: 750 g silica gel; eluting with 1 L each of 1-5% EtOAc / CH ₂ Cl ₂ ; one column: 250 g of silica gel; packaging with methylene chloride; loading 60 ml of the compound; elution with 2.5 and 5% EtOAc / CH ₂ Cl ₂ ), whereby the target compound (yield 87%) was obtained as orange solid, VRMS (M ⁺ ) for C ₁₅ H ₁₉ F ₂ N ₃ O ₄ : calc .: 3431343, found: 3431358.

 (c) 1- (tert-butoxycarbonyl) -4- [2,6-difluoro-4- (benzyloxycarbonyl) aminophenyl] piperazine.

1- (tert-Butoxycarbonyl) -4- (2,6-difluoro-4-nitrophenyl) piperazine (44.7 g, 130 mmol) was dissolved in 20% THF / MeOH (600 ml) in a 2 liter flask. Then, the ammonium format (41 g, 651 mmol) was added in portions to the mixture, after which 10% palladium on carbon (1.12 g, 2.5 wt%) was added, while cooling in an ice bath. After completion of the addition, the bath was removed. The contents of the flask were slightly heated, causing the yellow color to disappear. The completion of the reaction was monitored by TLC (30% EtOAc / hexane, shortwave UV) for 1.5 hours. After this, the reaction mixture was filtered through celite, and the filter cake was washed with 500 ml of MeOH. The filtrate was concentrated under reduced pressure to give a solid, which was treated with 1 L of EtOAc and 500 ml of water. The layers were separated, and the organic layer was washed with water (500 ml) and brine (500 ml). The aqueous portions were back extracted with additional EtOAc (2 x 300 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to give a yellow solid (40.8 g), which was immediately dissolved in dry DMF (500 ml) and cooled to -20 ^° C (in an ice / MeOH bath) in the atmosphere nitrogen. The resulting solution was treated with N, N-dimethylaniline (20.6 ml, 163 mmol), and then benzyl chloroformate (21.5 ml, 143 mmol) was added dropwise. An ice bath was left to thaw overnight. The completion of the reaction was monitored by TLC (30% EtOAc / Hex, shortwave UV). The mixture was concentrated to obtain a yellow oily substance, which was dissolved in 1 L EtOAc and washed with 500 ml of saline. The aqueous parts were back-extracted with additional EtOAc (2 x 300 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to give a yellow solid. This crude material was recrystallized from hot EtOAc / hexane to give 39.11 g (67%) of the target compound as a pale yellow crystalline solid, mp. 171-172 ^o C.

 (d) [3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol.

1- (tert-Butoxycarbonyl) -4- [2,6-difluoro-4- (benzyloxycarbonyl) aminophenyl] piperazine (14.05 g, 31 mmol) was dissolved in anhydrous THF (158 ml), and then cooled to -78 ^o C (in a dry ice / acetone bath). After this, n-butyllithium (21.6 ml, 35 mmol) was added dropwise to the reaction mixture over 25 minutes. This reaction mixture was allowed to stir for 30 minutes at -78 ^° C, after which (R) - (-) - glycidyl butyrate (4.89 ml, 35 mmol) was added dropwise over 7 minutes. The reaction mixture was maintained at -78 ^° C for another 15 minutes, and then the bath was removed and the mixture was slowly warmed to room temperature overnight. The completion of the reaction was monitored by TLC (5% MeOH / CHCl ₃ , shortwave UV). The resulting reaction mixture was diluted with 500 ml of methylene chloride, and then washed with water (Xx300 ml) and brine (300 ml). Aqueous portions were back extracted with additional CH ₂ Cl ₂ (3x400 ml). The combined organic extracts were dried with sodium sulfate, filtered and concentrated, resulting in a creamy yellow solid. This crude material was purified by recrystallization from hot EtOAc / hexane to give 11.063 g (85%) of the target compound as a white solid, mp 164-166 ^° C.

 (e) [[3- [3,5-difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -p-toluenesulfonate.

[[3-3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methanol (24.2 g, 59 mmol) was dissolved in pyridine ( 110 ml) and then cooled to 0 ^° C. in an ice bath. After this, freshly recrystallized p-toluenesulfonyl chloride (13.4 g, 70 mmol) was added, and the reaction mixture was allowed to stir for 2.5 hours at 0 ^° C. under a nitrogen atmosphere. The reaction flask was then closed with a stopper and stored in a refrigerator at 5 ^° C. overnight. During this time, the reaction mixture became a pale pink suspension. TLC detected the presence of a certain amount of alcohol. After that, the mixture was treated with 1.12 g of p-toluenesulfonyl chloride (5.85 mmol), a catalytic amount of 4- (dimethylamino) pyridine and 20 ml of anhydrous methylene chloride to facilitate stirring. After keeping the mixture for 4 hours at 0 ^° C., the reaction was completely completed, as indicated by TLC (5% MeOH / CH ₂ Cl ₃ , shortwave UV). Then 750 ml of ice water was added to the mixture, and the precipitated product was isolated by vacuum filtration, washing with 1 l of water and 500 ml of ether. After drying the product in vacuo, 29.921 g (90% yield) of the target compound are obtained in the form of a white solid, mp. 150.5-151.5 ^o C.

 (f) [[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] -2-oxo-5-oxazolidinyl] methyl] methanesulfonate.

[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl methanol (3.831 g, 9.27 mmol) was dissolved in methylene chloride (40 ml), cooled to 0 ^° C, and then treated with triethylamine (1.74 g, 2.4 ml, 17.22 mmol) in a nitrogen atmosphere. Then, methanesulfonyl chloride (1.48 g, 1 ml, 12.9 mmol) was slowly added over one minute. After half an hour, TLC analysis (20% acetone / CH ₂ Cl ₂ ) indicated complete completion of the reaction. The reaction mixture was diluted with methylene chloride (200 ml), washed with water (3x50 ml) and brine (50 ml), then dried over sodium sulfate, filtered and concentrated in vacuo, whereby the target compound was obtained in the form of an off-white solid, VRMS (M ⁺ ) for C ₂₀ H ₂₇ F ₂ N ₃ O ₇ S: calculated: 4911538, found: 4911543.

 (g) [[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] azide.

[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -p-toluenesulfonate (29.661 g, 52 mmol) was dissolved in dry DMF (125 ml), and then treated with solid NaN ₃ (10.19 g, 156 mmol) at room temperature. After that, the reaction mixture was heated to 60 ^° C. for 3 hours and allowed to cool to room temperature overnight under nitrogen. The completion of the reaction was monitored by TLC (30% EtOAc / hexane; two runs; shortwave UV). This reaction mixture was concentrated in vacuo to give a creamy, discolored solid. This crude product was dissolved in 600 ml EtOAc, and then washed with water (2x500 ml) and brine (500 ml). The aqueous fractions were back extracted with additional EtOAc (2x400 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 22.41 g (91%) of the target compound as a pale yellow solid, mp. 115-117 ^o C.

 Using essentially identical conditions, the corresponding mesylate was converted to the same azide.

 (h) N - [[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl methyl acetamide.

[[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] - 2-oxo-5-oxazolidinyl] methyl] azide (22.4 g, 51 mmol) was dissolved in 1 l of ethyl acetate, and then three times degassed with nitrogen. After this, 10% palladium charcoal (4.48 g, 20% by weight) was added, and the solution was again degassed three times with nitrogen, after which the nitrogen was replaced with hydrogen (balloon). After 3 hours, completion of the reaction was monitored by TLC (20% MeOH / CHCl ₃ , shortwave UV). Pyridine (8.26 ml, 102 mmol) was then added, after which the mixture was treated with acetic anhydride (9.64 ml, 102 mmol). The resulting reaction mixture was allowed to stir overnight at room temperature. The completion of the reaction was monitored by thin layer chromatography (20% MeOH / CHCl ₃ , shortwave UV radiation). Then the reaction mixture was filtered through celite, and the precipitate formed on the filter was washed with 500 ml of ethyl acetate. The filtrate was concentrated to a volume of approximately 600 ml, and then washed with water (2x500 ml) and brine (500 ml). The aqueous parts were back extracted with additional ethyl acetate (2 x 500 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to give a yellow solid. This crude product was recrystallized from hot CHCl ₃ and hexane to give 19.167 g (83%) of the target compound as a white solid, mp 177-179 ^° C.

 (i) N - [[3- [3,5-Difluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

N - [[3- [3,5-Difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (1.00 g, 2, 20 mM) was dissolved in methylene chloride (6 ml) and cooled to 0 ^° C. in an ice bath. After adding 20 ml of trifluoroacetic acid, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature for 1 h. After that, the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in water (15 ml). The resulting solution was added to the ion exchange resin AG-I-X8 (Bio Pad) (12 ml; OH ^- form; washed with water until neutralization). After adding 5 ml of water, the mixture was stirred for 10 minutes. Then the mixture was filtered, and the resin was washed with additional water (3x5 ml). This aqueous filtrate was lyophilized to give 0.559 g (72%) of the target compound as a white solid, mp. 108-112 ^o C (decomp.).

 (j) (S) -N - [[3- [3,5-Difluoro-4- [4- [2- (1-piperidinyl) ethyl] -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] acetamide.

A mixture of (S) -N - [[3- [3,5-difluoro-4- (1-piperazinyl) phenyl] - 2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g, 0.565 mmol), 1- monohydrochloride (2-chloroethyl) piperidine (0.125 g, 0.678 mmol) and potassium carbonate (0.478 g, 3.39 mmol) in acetonitrile (10 ml) were heated under reflux for one and a half hours. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with dichloromethane, the solids were filtered off, and the filtrate was concentrated in vacuo to give a whitish solid (0.248 g). This crude material was chromatographed on silica gel (5 g), eluting with 5% methanol / chloroform and then 10% methanol / chloroform. After concentrating the appropriate fractions, 0.137 g (52%) of the target compound was obtained in the form of an off-white solid, mp 198-200 ^o C.

Example 33. (S) -N - [[3- [3-fluoro-4- [4- [2- (1-piperidinyl) ethyl] -1-piperidinyl) ethyl] -1-piperazinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide
A mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g, 0.595 mmol), monohydrochloride 1- (2 -chloroethyl) piperidine (0.131 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 ml) were heated under reflux for 1 h. The resulting residue was triturated with hexane, cooled to room temperature and concentrated in a vacuum. The solids were filtered off and the filtrate was concentrated in vacuo to give a crude product (0.308 g). This crude material was chromatographed on 5 g of silica gel, eluting with 5% methanol / chloroform and then 10% methanol / chloroform. After concentrating the appropriate fractions, 0.192 g (72%) of the target compound was obtained in the form of an off-white solid, mp. 169-170 ^o C.

 Example 34. (S) -N - [[3- [3-fluoro-4- [4- [2- (4-morpholinyl) ethyl] -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide.

A mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g, 0.595 mmol), 4- (2 -chloroethyl) morpholine (0.133 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 ml) were heated under reflux for one hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids were filtered off, and the filtrate was concentrated in vacuo to give an amber-colored gum (0.21 g). This crude material was chromatographed on silica gel (5 g), eluting with 5% methanol / chloroform and then 10% methanol / chloroform. After concentrating the appropriate fractions, 0.129 g (48%) of the target compound was obtained in the form of an off-white solid, mp 150-151.5 ^o C.

 Example 35. (S) -N - [[3- [4- [2- (diethylamino) ethyl] -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

A mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g, 0.595 mmol), 2-diethylaminoethyl chloride hydrochloride ( 0.123 g, 0.714 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 ml) were heated under reflux for one hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with dichloromethane, the solids were filtered off, and the filtrate was concentrated in vacuo to give 0.241 g of an off-white gummy solid. This crude material was chromatographed on silica gel (5 g), eluting with 5% methanol / chloroform and then 10% methanol / chloroform. After concentration of the appropriate fractions, 0.159 g (61%) of the target compound was obtained as an off-white solid, mp. 131-133 ^o C.

 Example 36. (S) -N - [[3- [3-fluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

A mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.450 g, 1.34 mmol), 2-chloroethylmethyl ether (1.220 ml, 13.40 mmol) and potassium carbonate (1.110 g, 8.04 mmol) in acetonitrile (25 ml) were refluxed for 24 hours. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was triturated with dichloromethane, the solids were filtered off, and the filtrate was concentrated in vacuo to give a yellow foamy solid (0.326 g). This crude material was chromatographed on silica gel (25 g), eluting with 1% methanol / chloroform, 3% methanol / chloroform, and then 5% methanol / chloroform. After concentration of the appropriate fractions, 0.296 g (56%) of the target compound was obtained in the form of an off-white solid, mp 144.5-146 ^° C.

 Example 37. (S) -N - [[3- [3,5-Difluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

Solution (S) -N - [[3- [3,5-difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g , 0.441 mmol) in dichloromethane (1 ml) was treated with trifluoroacetic acid (4 ml) at room temperature for one hour. The reaction mixture was concentrated in vacuo, and the resulting residue was combined with 2-chloroethyl methyl ether (403 μl, 4.41 mmol), potassium carbonate (0.730 g, 5.28 mmol) and acetonitrile (9 ml), and the resulting mixture was heated under reflux. for 15 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated with dichloromethane, the solids were filtered off, and the filtrate was concentrated in vacuo to give a crude product. This crude material was chromatographed on silica gel (10 g), eluting with 1% methanol / chloroform, 3% methanol / chloroform, and then 5% methanol / chloroform. After concentrating the appropriate fractions, 0.097 g (53%) of the target compound was obtained as an off-white solid, mp. 162-164 ^o C.

 Example 38. (S) -N - [[3- [3-fluoro-4- [4- (3-hydroxypropyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

A mixture of (S) -N - [[3- [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.200 g, 0.595 mmol) 3-chloro-1- propanol (299 μl, 3.57 mmol) and potassium carbonate (0.493 g, 3.57 mmol) in acetonitrile (12 ml) were refluxed for 7 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting crude material was dissolved in 10% methanol / chloroform and adsorbed onto a layer of silica gel (2 g). The resulting residue was chromatographed on 10 g of silica gel, eluting with 1% methanol / chloroform, 3% methanol / chloroform, and then 6% methanol / chloroform. After concentration of the appropriate fractions, 0.096 g (41%) of the target compound was obtained in the form of a white solid, mp 154-155.5 ^o C.

 Example 39. (S) -N - [[3- [3,5-difluoro-4- [4- (2-hydroxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

Solution (S) -N - [[3- [3,5-difluoro-4- [4- (tert-butoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.400 g , 0.881 mmol) in dichloromethane (3 ml) at room temperature and 7 ml of trifluoroacetic acid were treated for an hour. The resulting reaction mixture was concentrated in vacuo, and the amber-colored syrup formed was combined with 2-chloroethanol (354 μl, 5.27 mmol), potassium carbonate (0.730 g, 5.27 mmol) and acetonitrile (20 ml). The resulting mixture was heated under reflux for 24 hours. After that, the mixture was cooled to room temperature and concentrated in vacuo. The resulting crude product was chromatographed on silica gel (10 g), eluting with 1% methanol / chloroform, 3% methanol / chloroform, and then 6% methanol / chloroform. After concentration of the appropriate fractions, 0.067 g (19% yield) of the target compound was obtained as an off-white solid, mp 172-174 ^° C.

 Example 40. (S) -N - [[3- [3-fluoro-4- [4- [3- (4-morpholinyl) -1-oxopropyl] -1-piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] acetamide.

3- (4-Morpholinyl) propionic acid (0.600 g, 2.11 mmol) obtained by condensing morpholine with ethyl acrylate (3 equivalents) in boiling ethanol and then by distillation, saponification (1 N aqueous sodium hydroxide solution; boiling tetrahydrofuran; ), neutralization (1 N HCl) and lyophilization, combined with 1,3-dicyclohexylcarbodiimide (0.434 g, 2.11 mmol), 4- (dimethylamino) pyridine (13 mg, 0.11 mmol), (S) -N - [[3 [3-fluoro-4- (1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.354 g, 1.05 mmol) and tetrahydrofuran / dichloromethane (1: 1) ( 50 ml) at room temperature. After 3 days, the reaction mixture was filtered to remove precipitated 1,3-dicyclohexylurea, and the filtrate was concentrated in vacuo. The resulting crude product was chromatographed on silica gel (20 g), eluting with a gradient of 1-6% methanol / chloroform, to give 0.446 g (95%) of the target compound as a white solid, mp 209-210 ^o C.

Claims (13)

1. Derived oxazolidinone of the formula I

or a pharmaceutically acceptable salt thereof, wherein n 1;
ring A represents a piperazine ring;
Y -C _{1 - 6} alkyl;
-C (O) -C _{1 - 6} alkyl; -C (O) -O-C _{1 - 6} -alkyl; benzoyl, 2-benzyloxyethoxycarbonyl; 1,4-dioxopentyl; -N (C _{1 - 4} -alkyl) _2, piperidinyl, morpholinyl, a group of formula

X and Z are independently C _{1 - 6} -alkyl or hydrogen,
wherein in each case said C _{1 - 6} alkyl may be substituted with one or more substituents selected from F, Cl, Br, CN or OR ^1, where R ¹ is hydrogen or C _{1 - 4} alkyl;
U, V and W are independently fluorine or hydrogen;
R lower alkyl;
q 0 4 inclusive.  2. The compound according to claim 1, where X and Z are hydrogen.  3. The compound according to claim 1, where U and V are fluorine, and W is hydrogen.  4. The compound according to claim 1, where U is fluorine, and V and W are hydrogen.  5. The compound according to claim 1, where Y is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, 2-chloroethoxycarbonyl, 2-hydroxyethoxycarbonyl, 2-benzyloxyethoxycarbonyl , 2-methoxyethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, cyanomethyl, 2-cyanoethyl, 2-fluoroethoxycarbonyl, tert-butoxycarbonyl.  6. The compound according to claim 4, where Y is methoxycarbonyl or cyanomethyl.  7. The compound according to claim 1, where R is methyl. 8. The compound according to claim 1, in which the optically pure enantiomer has the S-configuration at the C ₅ -oxazolidinone ring.  9. The compound according to claim 1, where n 1. 10. The compounds according to claim 1, which are:
(a) 4- (4- (5 - ((acetylamino) methyl) -2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid methyl ester;
(b) 4- (4- (5 - ((acetylamino) methyl) - 2-oxo-3-oxazolidinyl) -2-fluorophenyl) -1-piperazinecarboxylic acid ethyl ester;
(c) 4- (4- (5 - ((acetylamino) methyl) - 2-oxo-3-oxazolidinyl) phenyl) -1-piperazinecarboxylic acid methyl ester;
(d) N - ((2-oxo-3- (4- (phenylcarbonyl) -1-piperazinyl) phenyl) -5-oxazolidinyl) methyl) acetamide;
(e) N - ((3- (4- (3-fluoro-4- (2-cyanoethyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide;
(f) N - ((3- (4- (3-fluoro-4- (4- (2-hydroxyethyl) carbonyl-1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide;
(g) N - ((3- (4- (3-fluoro-4 - ((phenylcarbonyl) -1-piperazinyl)) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide;
(h) 4- [4- [5 - [(acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazinecarboxylic acid 2-methoxyethyl ester;
(i) 4- [4- [5- (acetylamino) methyl] -2-oxo-3-oxazolidinyl] -2-fluorophenyl] -1-piperazineacetonitrile;
(j) (±) -N - [[3- [4- [4- (1,4-dioxopentyl) -1-piperazinyl] -3-fluorophenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide;
(k) (S) -N - [[3- [3-fluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or
(l) (S) -N - [[3- [3,5-difluoro-4- [4- (2-methoxyethyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.  11. The compound according to any one of claims 1 to 10 as an active principle in the manufacture of a medicament for the treatment of microbial infections.  12. A method for treating microbial infections in warm-blooded animals, which method comprises administering from 0.1 to 100 mg / kg body weight per day of a compound of formula I as defined in claim 1 to said warm-blooded animal in need of such treatment.  13. The method of claim 12, wherein said compound is administered in an amount of 3-50 mg / kg body weight per day.

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